The two major objectives of this project are to: (1) develop a model of muscular fatigue based on alterations to membrane control of intracellular calcium (Ca ion) and (2) to elucidate the mechanisms by which the subcellular Ca ion transporting membranes are affected by fatigue. Two methods of inducing fatigue will be used. An in situ skeletal muscle preparation will be stimulated to exhaustion and studied. The second method will be to run the animals to exhaustion on a motor driven treadmill and then cardiac and skeletal muscles studied. Mitochondria and sarcoplasmic reticulum (SR) will be isolated from cardiac and skeletal muscles. Ca ion transport will be studied in both membrane systems using 45 Ca ion as a tracer and the millipore filtration technique. In mitochondria, respiration studies will be conducted simultaneously with Ca ion transport studies. Levels of Ca ion in the reaction media will be controlled with EGTA buffers. Exhaustive exercise leads to alterations in the Ca ion transport functions of mitochondria and SR. Ca ion transport by mitochondria from skeletal muscles appears to be elevated, while SR Ca ion transport is reduced in skeletal and cardiac muscles from exhausted animals. These observations suggest that the control of intracellular Ca ion concentrations may be altered during physical work. Such alterations could ultimately result in the inability of the muscle to develop the tension necessary to perform work. A complete understanding of the mechanisms of muscular fatigue will lead to a better understanding of basic muscle physiology and the development of improved clinical practices in rehabilitation medicine.